DE1966195C3 - Process for the preparation of 1-alkyl-2-aminomethylpyrrolidines - Google Patents

Description

(V)

^l - CH ₂ NH,

N
R ¹

Ii)

solved by using a l-alkyl-2-nitromethylene pyrrolidine of the general formula II

in which R ^{1 has} the above meaning, hydrogenated in methanol at atmospheric pressure and room temperature in the presence of Raney nickel.

The invention relates to a process for the preparation of 1-alkyl-2-aminomethylpyrrolidines of the general Formula 1)

in which R ^{1 is} an alkyl group.

l-ethyl-2-aminomethylpyrrolidine, according to the invention The preferred compound produced so far has been obtained by heating i-ethyl-3-chloropiperidine hydrochloride produced with ammonia according to US Pat. No. 3,031,452. However, this method creates 1-ethyl-3-hydroxypiperidine as a difficult-to-separate by-product. This method is therefore for manufacturing of intermediate products for pharmaceutical products that are present as substances of high purity must, not suitable. In contrast, the compounds prepared according to the invention can be used as intermediates can be used safely for medicinal products.

From j. Amer. Chem. Soc. 71, 2042 (1949) is a Process for the preparation of 1-ethyl-2-aminomethylpyrrolidine from l-ethyl-3-chloropiperidine by its Reaction with benzylamine and subsequent hydrogenolytic debenzylation of the 1-ethyl-2-benzylaminomethylpyrrolidine formed known. However, the preparation of the intermediate with benzylamine requires reaction times of 2 days at 65 to 75 ° C. There the debenzylation must also be carried out in the heat, this process requires a considerable amount Expenditure of working time and energy. In addition, only certain catalysts are used for debenzylation suitable.

The invention is directed to a process for the preparation of the aminomethylpyrrolidines mentioned at the beginning, in which the desired products from a cheap raw material with high purity and Yield as well as free of by-products can be obtained. This object is achieved according to the invention CH-NO,

N
R ¹

111)

in which R ^{1 has} the above meaning, hydrogenated in methanol at atmospheric pressure and room temperature in the presence of Raney nickel.

In view of the in the literature, e.g. B. J. A. C. F. 68, 624 (1946), described problems which occur in the hydrogenation of nitrostilbenes, is the easy one Feasibility of the method of the invention surprising.

Including its precursors, the process of the invention can be represented by the following reaction scheme, where R ^{1 is} as defined above, R ^{3 is} a low molecular weight alkyl group, R ^{J is} a straight-chain low molecular weight alkyl group and R ^{4 can be} an alkyl group.

t = O

N
R ¹

(I) (Ri) ₂ p

(R.;), OBF ₄
(21 R ₄ OM
(. ¹ I) CH ₁ NO ₂

^ = CHNO ₂

R-

Ranc \ -nickel

(11)

or

(V)

CH ₁ NH,

The first stage of the process for the preparation of the starting compound of the general formula V consists of the reaction of the l-alkyl-2-pyirolidinone (II) with the dialkyl sulfate (111) or the trialkyloxonium tetrafluoroborate (IV) and the alkali metal alcoholate and nitromethane to form the compound ( V). The radical R 'can be a methyl, ethyl, propyl, isopropyl or butyl group or the like. The radical R ^{2 of} the dialkyl sulfate (III) can be a lower alkyl group, e.g. B. be a methyl, ethyl or propyl group or the like. The reaction of the l-alkyl-2-pyrrolidinone (II) with the dialkyl sulfate (III) does not require a solvent, but can also be carried out in

Solvents such as ether, methanol, ethanol, benzene or the like can be carried out. The reaction temperature is narrow and becomes ordinary carried out at room temperature or with heating

The reaction of the l-alkyl-2-pyrroidinone (II) with the Trialkyloxonium fluoroborate (IV) (cf. H. Meerwein and coworkers, Chem. Ber. 89 [1956], p. 2074) can with or without solvents. Ether, benzene or the like can be used as the solvent will. The reaction temperature can be varied within a wide range, but is usually at Carried out at room temperature or with heating.

The group R ^{3 of} the trialkyloxonium tetrafluoroborate (IV) can be a straight-chain lower alkyl radical, e.g. B. a methyl or ethyl group. The trialkyloxonium compound (IV) is usually prepared in situ, e.g. B. by adding l ^ -EpoxyO-chloropropane dropwise to a solution of boron trifluoride etherate (BF3-OR ³ 2 with the above meanings for R ³ ) in ether at room temperature while stirring, the reaction mixture is gently heated under reflux, the ether is decanted off when the trialkyloxonium tetrafluoroborate begins to precipitate and solidify, washing the residue with anhydrous ether.

The above reaction is generally carried out in a solvent, usually being used an anhydrous ether as a reagent and solvent. The ether can also be used in combination with other solvents, e.g. B. with anhydrous benzene, anhydrous dioxane and anhydrous dichloroethylene, can be used.

The compounds thus obtained are then treated with an alkali metal alcoholate obtained from an alcohol, such as methanol, ethanol, propanol, isopropanol or butanol, and an alkali metal such as sodium or Potassium, reacted. This reaction is usually carried out in a solvent. A's solvent alcohol is generally used, but other solvents which are inert with respect to the reaction can also be used be used. The reaction temperature can be varied over a wide range, the The reaction is usually carried out with cooling, at room temperature or with heating.

The compound thus obtained can be isolated and purified, but it can also can be used directly for the following reaction.

The subsequent reaction of the compound with nitromethane is with or without a solvent carried out. Usually, the solvent used in the previous reaction step becomes without Exchange continued to be used. The reaction temperature can be varied within a wide range, the The reaction is usually carried out with cooling, at room temperature or with heating.

The i-alkyl-2-nitromethylene pyrrolidine thus obtained of the general formula (V) can be isolated and purified, but it can also be without Isolation and purification of the following hydrogenation are fed.

The 1-alkyl-2-aminomethylpyrrolidine obtained according to the invention of the general formula (I) can be converted into salts of inorganic acids, such as. B. hydrochloric acid. Hydrobromic acid, Sulfuric acid, or of organic acids, such as. B. oxalic acid, tartaric acid, and maleic acid Picric acid are transferred.

The invention is explained in more detail below on the basis of exemplary embodiments.

Example 1 J
1-ethyl-2-aminomethylpyrixjlidin

To a solution of 23.4 g of l-ethyl-2-nitromethylene-ί pyrrolidine in 500 ml of methanol, 5 g of Raney nickel are added. The resulting mixture is at Hydrogenated atmospheric pressure and room temperature for about 5 hours, leaving 4 molar equivalents of hydrogen are consumed. The reaction mixture becomes

filtered to remove the Raney nickel, and the solvent evaporated under reduced pressure. The residue is distilled, obtaining 15.7 g of l-ethyl-2-aminomethyIpyrrolidin than one boiling at 58 to 60 ⁰ C and 16 mm Hg oil.

r, The gas-liquid chromatogram of this substance shows a single peak. The infrared spectrum is identical to the spectrum of a sample made according to that described in US Pat. No. 3,031,452 Process was established.

The preparation of starting compounds is explained below.

a) l-ethyl-2-pyrrolidinone

To a solution of 13.4 g of 1-vinyl-2-pyrrolidinone in 3 g of Raney nickel are added to 70 ml of methanol. The resulting mixture is at atmospheric pressure and Hydrogenated room temperature for 2 hours, one mole equivalent of hydrogen being consumed. the The reaction mixture is filtered to remove the Raney nickel and the methanol is reduced at reduced pressure Pressure evaporates. The residue is distilled and yields 12.6g of 1-ethyl-2-pyrrolidinone as a at 84 up to 88 ° C and boiling oil at 15 mm Hg.

For the hydrogenation of l-vinyl-2-pyrrolidinone The catalysts mentioned for the hydrogenation of 1-nitromethylene pyrrolidine (V) and the solvents mentioned there are used. The hydrogen pressure can be in a wide range of Atmospheric pressure can be varied up to high pressure, but with a pressure between atmospheric Pressure and a few atmospheres are sufficient for the reduction. The reaction will stop as soon as the calculated amount of hydrogen is consumed by considering the type and amount of catalyst den The outlet pressure of the hydrogen, the reaction temperature, the reaction time and the like controls. The reaction product can by filtering off the catalyst and subsequent evaporation of the solvent can be isolated and, if desired, purified. However, it can can also be used for the following reaction without purification.

b) 1-ethyl-2-nitromethylene pyrrolidine

A solution of 11.3 g of l-ethyl-2-pyrrolidinone in 12.6 g of dimethyl sulfate is stirred for 172 hours heated to a temperature of 60 to 63 ° C for a long time. The mixture obtained in this way is under Stir and cool added dropwise to a sodium methylate solution, which was obtained by dissolving 2.3 g Sodium in 70 ml of anhydrous methanol. The resulting mixture is 30 minutes long stirred. 9.2 g of nitromethane are then added to this mixture, and after further stirring of 1 hour at room temperature, the mixture is left to stand overnight. The methanol is through Removed evaporation at reduced pressure, the residue mixed with 150 ml of water and then

extracted three times with a total of 150 ml of chloroform. The chloroform. «- it is dried, anhydrous ether are gradually added dropwise 22.2 g of 1,2-epoxy-3-chloropropane at room temperature added with stirring. The resulting mixture is stirred for 2 hours at room temperature

The ether is removed by decanting and the residue is washed several times with anhydrous ether washed. The thus obtained triethyloxonium fluoroborate is added dropwise while cooling with ice 22.6 g of 1-ethyl-2-pyrrolidinone were added. The emerging The mixture is stirred at room temperature for 30 minutes and then left to stand for 2 hours. The ether which forms during the reaction is removed by decantation and the residue is added dropwise added to a solution of 5.0 g of sodium in 100 ml of anhydrous ethanol with cooling. the obtained solution is stirred for 30 minutes at the same temperature and then while cooling with ice with 18.0 g of nitromethane mixed. The mixture is stirred at room temperature for 3 hours, then over Left to stand overnight, the ethanol removed by evaporation under reduced pressure, the residue with «Vtsser washed and then extracted with chloroform. The chloroform layer is dried and evaporated under reduced pressure. The residue will washed with ether. 27.2 g of 1-ethyl-2-nitromethylene pyrrolidine are obtained in the form of crystals that melt at 125 to 127 ° C.

λ!,:.: · "349ηιμ (ε28 300)

Analysis calculated for C7H12N2O2:

Calculated: C 53.83, H 7.74, N 17.91;

Found: C 54.12, H 7.85. N 17.98.

Example 2
1-methyl-2-aminomethylpyrrolidine

1-Methyl ^ -nitromethylene pyrrolidine in methanol is treated in the same way as in Example 1. 1-methyl-2-aminomethylpyrrolidine is obtained in the form of an oil. that boils at 56 ⁰ C at 18 mm Hg.

Preparation of the starting compound
1-methyl-2-nitromethylene pyrrolidine

To a solution of 91 g of boron trifluoride etherate in 300 ml of anhydrous ether, 44.5 g are added dropwise 1,2-EDoxy-3-chloropropane was added at room temperature and with stirring. The mixture obtained is stirred at room temperature for 2 hours, the ether is removed by decarting and the residue washed several times with anhydrous ether. The thus obtained triethyloxonium fluoroborate is added dropwise with ice-cooling to 39.6 g of 1-methyl-2-pyrrolidinone added. The resulting mixture is stirred at room temperature for 30 minutes and then left for 2 hours. The ether that forms during the reaction is decanted removed and the residue tropfe.iweise to a solution of 10 g of sodium in 200 ml of anhydrous Given ethanol with cooling.

The resulting solution is stirred for 30 minutes at the same temperature and then while cooling with ice mixed with 36.0 g of nitromethane, the mixture was stirred at room temperature for 3 hours and over Left for the night. The ethanol is removed by evaporation under reduced pressure. Of the The residue is washed with water and then extracted with chloroform. The chlorolorm layer will dried, evaporated under reduced pressure and the residue washed with ether. You get 44 g of l-methyl-2-nitromethylene pyrrolidine in the form of Crystals that melt at 154 ° C.

Example 3
1-butyl-2-aminomethylpyrrolidine

35 g of l-butyl-2-nitromethylene pyrrolidine, dissolved in 250 ml, are treated in a hydrogenation apparatus Methanol, with 6 g of Raney nickel and hydrogen. 17 liters of hydrogen are absorbed in 7 hours. It is filtered to remove the catalyst,

the methanol evaporates and a yellowish-red oil is obtained, which distills ^{at 104 ° C. and 22 mm Hg.} The refractive index at 20 ° C. is 1.4633 (weight = 20 g, yield = 67%).

Preparation of the starting compound
1-butyl-2-nitromethylene pyrrolidine

In a 1-liter flask equipped with mechanical stirrer, condenser and thermometer is heated increasing 70.5 g of 1-Butyipyrrolidinon (0.5 mol) of dimethyl sulfate and 63 g (0.5 mol) for 30 minutes at 6O ⁰ C. It is cooled to + 15 ^° C. and a solution of 350 ml of sodium methyl octet (prepared with 11.5 g of sodium and 350 ml of methanol) is added. The mixture is stirred for 30 minutes and 46 g of nitromethane are added dropwise with stirring over the course of 2 hours. The mixture is left to stand overnight, the solvent is removed in vacuo, the crystallized residue is taken up in a mixture of water and chloroform (50:50) and, after drying, the chloroform phase is extracted with magnesium sulfate

r> and removal of the solvent gives l-butyl-2-nitromethylene pyrrolidine with a melting point. from 67 ° C.

Yield: 63%

B e i s ρ i e I 4

N-isobutyl-2-aminomethylpyrrolidine

In which, as carried out in Example 1, hydrogenation of the compound 26 g (yield 80%) is obtained of a <r> oil which oei distilled 109 ° C and 7 mm Hg and is the refractive index at 20 ⁰ C 1.4612.

Preparation of the starting compound
l-isobutyl-2-nitromethylene pyrrolidine

In a 1-liter flask equipped with sealed mechanical stirrer, condenser and thermometer ascending was heated at 6O ⁰ C 70.5 g of N-Isobutylpyrrolidinon and 63 g of dimethyl sulfate. The procedure is as in Example 1 and 38 g of N-isobutyl-2-nitromethylene pyrrolidine with a melting point of 59 ° C. are obtained. Yield: 54%.

Example 5
1-propyl-2-aminomethylpyrrolidine

47 g of 1-propyl-2-nitromethylene pyrrolidine are placed in a hydrogenation apparatus diluted with 600 ml of methanol and added 10 g of Raney nickel. In 12 hours it will be 24 liters of hydrogen added. It is filtered to remove the catalyst and the methanol is distilled away. 1-Propyl-2-ainomethylpyrrolidine is obtained in In the form of a yellow-red oil (33 g) with a refractive index of 1.4650 at 20 ° C.

19 65 195

Preparation of the starting compound
i-propyi-2-nitromethylene pyrrolidine

63 g of dimethyl sulfate and 63.5 g of i-propylpyrruiidinop are heated at GCTC for 30 minutes in a 1 liter flask with a mechanically sealed guide, exposed condenser and thermometer. It is cooled; uf from +15 ⁰ C and add 350 ml Natriummethyla; (made with 13.5 g sodium and 350 ml methanol). Then stir for another 30 minutes, add

46 g of nilromethane are added dropwise and the temperature is reduced to 20 ° C terminate. Leave to stand overnight and distill! dai Solvent off. With an extraction mixture of water / chloroform, 1-propyl-2-nitromethylene pyrrolidine is obtained, M.p. 91 ° C. Yield: 55.3%.

The isomeric 1-isopropyl-2-aminomethylpyrroiidine can be obtained in an analogous manner in a yield of 70% and with a melting point of 83 ° C and is hydrogenated accordingly.

Claims (1)

Claim: Process for the preparation of 1-alkyl-2-ainomethylpyrrolidines of the general formula I. -CH ₁ NH, (I) in which R ^{1 is} an alkyl group, characterized in that an 1-alkyl-2-nitromethylene pyrrolidine of the general formula V